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Lack of additive role of ageing in nigrostriatal neurodegeneration triggered by α-synuclein overexpression.

Bourdenx M, Dovero S, Engeln M, Bido S, Bastide MF, Dutheil N, Vollenweider I, Baud L, Piron C, Grouthier V, Boraud T, Porras G, Li Q, Baekelandt V, Scheller D, Michel A, Fernagut PO, Georges F, Courtine G, Bezard E, Dehay B - Acta Neuropathol Commun (2015)

Bottom Line: However, phenotypic mutants with either accelerated senescence or resistance to senescence did not display differential susceptibility to hα-syn overexpression.Unlike mice, monkeys did not exhibit correlations between levels of phosphorylated α-syn and neurodegeneration.Ageing, however, neither exacerbated nigrostriatal neurodegeneration nor α-syn pathology per se.

View Article: PubMed Central - PubMed

Affiliation: University de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux, France.

ABSTRACT

Introduction: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons as well as the presence of proteinaceous inclusions named Lewy bodies. α-synuclein (α-syn) is a major constituent of Lewy bodies, and the first disease-causing protein characterized in PD. Several α-syn-based animal models of PD have been developed to investigate the pathophysiology of PD, but none of them recapitulate the full picture of the disease. Ageing is the most compelling and major risk factor for developing PD but its impact on α-syn toxicity remains however unexplored. In this study, we developed and exploited a recombinant adeno-associated viral (AAV) vector of serotype 9 overexpressing mutated α-syn to elucidate the influence of ageing on the dynamics of PD-related neurodegeneration associated with α-syn pathology in different mammalian species.

Results: Identical AAV pseudotype 2/9 vectors carrying the DNA for human mutant p.A53T α-syn were injected into the substantia nigra to induce neurodegeneration and synucleinopathy in mice, rats and monkeys. Rats were used first to validate the ability of this serotype to replicate α-syn pathology and second to investigate the relationship between the kinetics of α-syn-induced nigrostriatal degeneration and the progressive onset of motor dysfunctions, strikingly reminiscent of the impairments observed in PD patients. In mice, AAV2/9-hα-syn injection into the substantia nigra was associated with accumulation of α-syn and phosphorylated hα-syn, regardless of mouse strain. However, phenotypic mutants with either accelerated senescence or resistance to senescence did not display differential susceptibility to hα-syn overexpression. Of note, p-α-syn levels correlated with nigrostriatal degeneration in mice. In monkeys, hα-syn-induced degeneration of the nigrostriatal pathway was not affected by the age of the animals. Unlike mice, monkeys did not exhibit correlations between levels of phosphorylated α-syn and neurodegeneration.

Conclusions: In conclusion, AAV2/9-mediated hα-syn induces robust nigrostriatal neurodegeneration in mice, rats and monkeys, allowing translational comparisons among species. Ageing, however, neither exacerbated nigrostriatal neurodegeneration nor α-syn pathology per se. Our unprecedented multi-species investigation thus favours the multiple-hit hypothesis for PD wherein ageing would merely be an aggravating, additive, factor superimposed upon an independent disease process.

No MeSH data available.


Related in: MedlinePlus

Behavioral impairments associated with hα-syn overexpression in rats. a Spontaneous locomotor activity at baseline (Bsl) and at 4, 8, 12 and 16 weeks after surgery. b Stepping test at baseline and at 4,8,12 and 16 weeks after surgery. c Color-coded stick diagram decomposition of hindlimb movement for a representative healthy and AAV-hα-syn rat during crossing of an elevated horizontal ladder with irregularly spaced rungs (spacing 5.2 +/− 0.3 cm). The corresponding endpoint trajectory is shown below. The colour code indicated the instantaneous velocity of the endpoint, while the arrows report the orientation and intensity of the foot push-off at swing onset. Light grey: stance; dark grey: hit; yellow: slip; dark red: miss. d Pie charts summarize total percentage of hits, slips, and misses (total of 182 steps evaluated, n are indicated in the legend boxes). Below percentage of hits, slips and misses are quantified as histogram plots. e The same representation is shown for a representative healthy and Parkinsonian rat during overground locomotion. f Principal component (PC) analysis was applied on 89 gait parameters measured during overground locomotion (10–15 gait cycles/hindlimb/rat, n = 4 healthy and n = 6 AAV-hα-syn rats). Each gait cycle is represented as a dots in the new space created by PC1–3. Histogram plot depicts mean values of PC1 scores for each experimental group. g Histogram plots represent mean values of parameters with high factor loading (/factor loading/ > 0.5) on PC1, illustrating the most salient differences in motor control between the two groups. Numbers refer to Additional file 1: Table S1. *p < 0.05; **p < 0.01; ***p < 0.001; $ p < 0.05 vs 4 weeks time point; error bars, SEM; PC, Principal Component; a.u., arbitrary unit
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Fig2: Behavioral impairments associated with hα-syn overexpression in rats. a Spontaneous locomotor activity at baseline (Bsl) and at 4, 8, 12 and 16 weeks after surgery. b Stepping test at baseline and at 4,8,12 and 16 weeks after surgery. c Color-coded stick diagram decomposition of hindlimb movement for a representative healthy and AAV-hα-syn rat during crossing of an elevated horizontal ladder with irregularly spaced rungs (spacing 5.2 +/− 0.3 cm). The corresponding endpoint trajectory is shown below. The colour code indicated the instantaneous velocity of the endpoint, while the arrows report the orientation and intensity of the foot push-off at swing onset. Light grey: stance; dark grey: hit; yellow: slip; dark red: miss. d Pie charts summarize total percentage of hits, slips, and misses (total of 182 steps evaluated, n are indicated in the legend boxes). Below percentage of hits, slips and misses are quantified as histogram plots. e The same representation is shown for a representative healthy and Parkinsonian rat during overground locomotion. f Principal component (PC) analysis was applied on 89 gait parameters measured during overground locomotion (10–15 gait cycles/hindlimb/rat, n = 4 healthy and n = 6 AAV-hα-syn rats). Each gait cycle is represented as a dots in the new space created by PC1–3. Histogram plot depicts mean values of PC1 scores for each experimental group. g Histogram plots represent mean values of parameters with high factor loading (/factor loading/ > 0.5) on PC1, illustrating the most salient differences in motor control between the two groups. Numbers refer to Additional file 1: Table S1. *p < 0.05; **p < 0.01; ***p < 0.001; $ p < 0.05 vs 4 weeks time point; error bars, SEM; PC, Principal Component; a.u., arbitrary unit

Mentions: The extent of lesion observed suggested that AAV-hα-syn-injected rats might develop overt parkinsonism. While AAV-hα-syn-injected rats displayed a significant decrease in spontaneous activity (Fig. 2a) from 8 weeks post-surgery onwards, they showed a significant decrease in the number of adjusting steps as early as 4 weeks and thereafter (Fig. 2b).Fig. 2


Lack of additive role of ageing in nigrostriatal neurodegeneration triggered by α-synuclein overexpression.

Bourdenx M, Dovero S, Engeln M, Bido S, Bastide MF, Dutheil N, Vollenweider I, Baud L, Piron C, Grouthier V, Boraud T, Porras G, Li Q, Baekelandt V, Scheller D, Michel A, Fernagut PO, Georges F, Courtine G, Bezard E, Dehay B - Acta Neuropathol Commun (2015)

Behavioral impairments associated with hα-syn overexpression in rats. a Spontaneous locomotor activity at baseline (Bsl) and at 4, 8, 12 and 16 weeks after surgery. b Stepping test at baseline and at 4,8,12 and 16 weeks after surgery. c Color-coded stick diagram decomposition of hindlimb movement for a representative healthy and AAV-hα-syn rat during crossing of an elevated horizontal ladder with irregularly spaced rungs (spacing 5.2 +/− 0.3 cm). The corresponding endpoint trajectory is shown below. The colour code indicated the instantaneous velocity of the endpoint, while the arrows report the orientation and intensity of the foot push-off at swing onset. Light grey: stance; dark grey: hit; yellow: slip; dark red: miss. d Pie charts summarize total percentage of hits, slips, and misses (total of 182 steps evaluated, n are indicated in the legend boxes). Below percentage of hits, slips and misses are quantified as histogram plots. e The same representation is shown for a representative healthy and Parkinsonian rat during overground locomotion. f Principal component (PC) analysis was applied on 89 gait parameters measured during overground locomotion (10–15 gait cycles/hindlimb/rat, n = 4 healthy and n = 6 AAV-hα-syn rats). Each gait cycle is represented as a dots in the new space created by PC1–3. Histogram plot depicts mean values of PC1 scores for each experimental group. g Histogram plots represent mean values of parameters with high factor loading (/factor loading/ > 0.5) on PC1, illustrating the most salient differences in motor control between the two groups. Numbers refer to Additional file 1: Table S1. *p < 0.05; **p < 0.01; ***p < 0.001; $ p < 0.05 vs 4 weeks time point; error bars, SEM; PC, Principal Component; a.u., arbitrary unit
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4513748&req=5

Fig2: Behavioral impairments associated with hα-syn overexpression in rats. a Spontaneous locomotor activity at baseline (Bsl) and at 4, 8, 12 and 16 weeks after surgery. b Stepping test at baseline and at 4,8,12 and 16 weeks after surgery. c Color-coded stick diagram decomposition of hindlimb movement for a representative healthy and AAV-hα-syn rat during crossing of an elevated horizontal ladder with irregularly spaced rungs (spacing 5.2 +/− 0.3 cm). The corresponding endpoint trajectory is shown below. The colour code indicated the instantaneous velocity of the endpoint, while the arrows report the orientation and intensity of the foot push-off at swing onset. Light grey: stance; dark grey: hit; yellow: slip; dark red: miss. d Pie charts summarize total percentage of hits, slips, and misses (total of 182 steps evaluated, n are indicated in the legend boxes). Below percentage of hits, slips and misses are quantified as histogram plots. e The same representation is shown for a representative healthy and Parkinsonian rat during overground locomotion. f Principal component (PC) analysis was applied on 89 gait parameters measured during overground locomotion (10–15 gait cycles/hindlimb/rat, n = 4 healthy and n = 6 AAV-hα-syn rats). Each gait cycle is represented as a dots in the new space created by PC1–3. Histogram plot depicts mean values of PC1 scores for each experimental group. g Histogram plots represent mean values of parameters with high factor loading (/factor loading/ > 0.5) on PC1, illustrating the most salient differences in motor control between the two groups. Numbers refer to Additional file 1: Table S1. *p < 0.05; **p < 0.01; ***p < 0.001; $ p < 0.05 vs 4 weeks time point; error bars, SEM; PC, Principal Component; a.u., arbitrary unit
Mentions: The extent of lesion observed suggested that AAV-hα-syn-injected rats might develop overt parkinsonism. While AAV-hα-syn-injected rats displayed a significant decrease in spontaneous activity (Fig. 2a) from 8 weeks post-surgery onwards, they showed a significant decrease in the number of adjusting steps as early as 4 weeks and thereafter (Fig. 2b).Fig. 2

Bottom Line: However, phenotypic mutants with either accelerated senescence or resistance to senescence did not display differential susceptibility to hα-syn overexpression.Unlike mice, monkeys did not exhibit correlations between levels of phosphorylated α-syn and neurodegeneration.Ageing, however, neither exacerbated nigrostriatal neurodegeneration nor α-syn pathology per se.

View Article: PubMed Central - PubMed

Affiliation: University de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux, France.

ABSTRACT

Introduction: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons as well as the presence of proteinaceous inclusions named Lewy bodies. α-synuclein (α-syn) is a major constituent of Lewy bodies, and the first disease-causing protein characterized in PD. Several α-syn-based animal models of PD have been developed to investigate the pathophysiology of PD, but none of them recapitulate the full picture of the disease. Ageing is the most compelling and major risk factor for developing PD but its impact on α-syn toxicity remains however unexplored. In this study, we developed and exploited a recombinant adeno-associated viral (AAV) vector of serotype 9 overexpressing mutated α-syn to elucidate the influence of ageing on the dynamics of PD-related neurodegeneration associated with α-syn pathology in different mammalian species.

Results: Identical AAV pseudotype 2/9 vectors carrying the DNA for human mutant p.A53T α-syn were injected into the substantia nigra to induce neurodegeneration and synucleinopathy in mice, rats and monkeys. Rats were used first to validate the ability of this serotype to replicate α-syn pathology and second to investigate the relationship between the kinetics of α-syn-induced nigrostriatal degeneration and the progressive onset of motor dysfunctions, strikingly reminiscent of the impairments observed in PD patients. In mice, AAV2/9-hα-syn injection into the substantia nigra was associated with accumulation of α-syn and phosphorylated hα-syn, regardless of mouse strain. However, phenotypic mutants with either accelerated senescence or resistance to senescence did not display differential susceptibility to hα-syn overexpression. Of note, p-α-syn levels correlated with nigrostriatal degeneration in mice. In monkeys, hα-syn-induced degeneration of the nigrostriatal pathway was not affected by the age of the animals. Unlike mice, monkeys did not exhibit correlations between levels of phosphorylated α-syn and neurodegeneration.

Conclusions: In conclusion, AAV2/9-mediated hα-syn induces robust nigrostriatal neurodegeneration in mice, rats and monkeys, allowing translational comparisons among species. Ageing, however, neither exacerbated nigrostriatal neurodegeneration nor α-syn pathology per se. Our unprecedented multi-species investigation thus favours the multiple-hit hypothesis for PD wherein ageing would merely be an aggravating, additive, factor superimposed upon an independent disease process.

No MeSH data available.


Related in: MedlinePlus